More Evidence of a Role for Transposons in Aging
Of late researchers have been investigating a possible role for transposable elements, or transposons, in degenerative aging. These are DNA sequences that can move around in the genome, and the incidence of such movement increases with age. This fits in with the general consensus that stochastic mutation of nuclear DNA is a cause of aging, through disarray of normal cellular operations. This view is disputed in some quarters by the suggestion that outside of cancer risk the effect isn't significant over the present human life span in comparison to other forms of damage. In the case of transposons, whether it is a cause or consequence of other age-related changes in cellular biology is still up for debate. The work here adds a little more to the evidence already in hand:
A new study increases and strengthens the links that have led scientists to propose the "transposon theory of aging." Transposons are rogue elements of DNA that break free in aging cells and rewrite themselves elsewhere in the genome, potentially creating lifespan-shortening chaos in the genetic makeups of tissues. As cells get older, prior studies have shown, tightly wound heterochromatin wrapping that typically imprisons transposons becomes looser, allowing them to slip out of their positions in chromosomes and move to new ones, disrupting normal cell function. Meanwhile, scientists have shown that potentially related interventions, such as restricting calories or manipulating certain genes, can demonstrably lengthen lifespans in laboratory animals. "In this report the big step forward is towards the possibility of a true causal relationship. So far there have been associations and suggestions that to all of us make sense, but you need the data to back up your opinion."
In one set of experiments, the team visually caught transposable elements in the act of jumping around in fruit flies as they aged. They inserted special genetic snippets into fat body cells, the equivalent of human liver and fat cells in flies that would glow bright green when specific transposable elements move about in the genome. Under the microscope the scientists could see a clear pattern of how the glowing "traps" lit up more and more as the flies aged. The increase in transposon activity was not steady as flies grew older. The data show that the timeframe in which transposable element activity really begins to increase is tightly correlated with the time when the flies start to die. Several experiments in the paper also show that that a key intervention already known to increase lifespan, a low-calorie diet, dramatically delays the onset of increased transposon activity.
To further explore the connection between transposon expression and lifespan, the team tested the effects of manipulating genes known to improve heterochromatin repression that are not only found in flies, but also in mammals. For example, increasing expression of the gene Su(var)3-9, which helps form heterochromatin, extended maximal fly lifespan from 60 to 80 days. Increasing expression of a gene called Dicer-2, which uses the small RNA pathway to suppress transposons, added significantly to lifespan as well. For all the new results, the researchers say it's still not quite time to declare outright that transposons are a cause of aging's health effects. But new experiments are planned. For example, the team will purposely encourage expression of transposable elements to see if that undermines health and lifespan. Another approach could be to use the powerful CRISPR gene editing technique to specifically disable the ability of transposable elements to mobilize within the genome. If that intervention affected lifespan, it would be telling as well.
George Church's group recently used CRISPR to remove the know retro transposing from pig embryos. I wonder if someone is thinking about doing this in fruit flies or another animal model to see if it has an effect on lifespan or cancer rates?
Despite Aubrey De Grey's initial assertion that DNA damage is not important in aging with the current human lifespan, there have been multiple fronts showing at least strong correlation and in cases like this, likely causation, since then (particularly in the field of transposon/retrotransposon activation from this lab at Brown as well as Josh Dubnau's lab at Cold Spring Harbor). This is even in flies, animals with over a 100 fold shorter lifespan than humans.
I know that SENS' assertion is largely about prioritizing, and the difficulty of addressing the question of DNA damage relative to biochemical damage such as glucosepane. But Aubrey De Grey's work was originally revolutionary because it was the first work to escape the narrow minded scientific majority and say that all damage in aging is valid. Do we really want to be the new conservatism in aging science? Especially since transposon and retrotransposon's are very much targetable, both by augmenting current defense pathways that fail in aging and (ideally) removal with CRISPR in the near future.
@Jim: remember that Church has thus far "only" been able to remove retroviruses from porcine kidney cells. There remain challenges to in vivo delivery of the CRISPR/Cas9 system for most purposes, and while no new genetic material would be needed, doing what he did in humans has challenenges of its own. To get it to work, they had to deliver not one but two inducible Cas9 guide RNAs into the cells, using either a lentivirus or PiggyBac transposon system, neither of which you'd want to use for therapeutic purposes. Additionally, the efficiency initially wasn't great, and they suspect but don't know that the problem was nonspecific DNA damage by CRISPR/Cas9 itself, which is obviously unacceptable for therapeutic purposes.
Additionally, one thing that made their job easier was that they determined that all the PERVs in the cell line relied on the same reverse transcriptase for viral replication and infection, so they were able to target them all using one system; the same might not prove true for human retrotransposons.
@Kris: to be clear, Dr. de Grey's view has never been that DNA damage has no harmful effects aging within the current human lifespan, but rather that we have foreseeable, workable solutions to all of the problems that it does cause: ablation for senescent cells, cell therapy to replace cells lost to apoptosis or senescence, and ablating the telomere-maintenance machinery as the ultimate cancer prophylactic. So far the studies on retrotransposons in mammalian aging are consistent with their reactivation being involved in cancer and as being capable of inducing senescence (but also that senescence may shut down retrotransposons); the question of their possible role in a kind of "general cellular malaise" caused by aberrant gene expression, in a large enough percentage of cells in a given tissue to induce dysfunction, remains open, though the theory predicts that they would not cause such effects.
There's pretty good current evidence that the age-
(That last line is copy-paste detritus).
@Michael: I agree that cell ablation/cell therapy are the more straightforward option in both these cases, but we also can't ignore the elephant in the room, the fact that neurons with DNA damage cannot be ablated/replaced without repercussions. That's one reason this makes sense to me as a parallel line of study alongside the more immediate promises of SENS research, and stands clearly above the igf-1/mtor stuff in terms of long term promise.
It also feels more pressing than other DNA damage research in that retrotransposons actively reproduce and thus cause an effect with is compounded, not linear over time.
Hi Kris,
First: generally, neurons don't go senescent (nor are they the origin cell for all but a tiny fraction of brain cancers (most originate in neural stem cells or glia)), so we wouldn't be ablating them. And remember, neurons are going to be lost via apoptosis, unrepaired aging damage, ministrokes, and trauma (including as we have learned very mild concussive events), so we're going to have to develop mature and reliable neural cell replacement therapy anyway. It's generally accepted that memory and identity don't reside in individual neurons but in the circuits in which they play a part, so the key is continuously generating such neurons and integrating them into such circuits, whatever the reason for their loss or dysfunction.
If, indeed, retrotransposons are a meaningful cause of non-cancer, non-cell-loss, non-senescent dysfunction in substantial numbers of aging neurons, their loss or being offline will still be remediable with ongoing cell therapy, provided that they are neither actively toxic to other cells in some way nor accumulate in catastrophic numbers without apoptosing or senescing. If something in that set of reasonable assumptions does not hold, of course we will have to develop strategies: Jim's gene therapy approach seems a good one, but one that will definitely require a lot of work. But we shouldn't panic unless and until we actually know such dysfunctional cells are accumulating in significant numbers, and there's not evidence for that yet.